1. Field of the Invention
The present invention relates to 4-alkyl-2-haloaniline derivatives and a process for producing the same. The 4-alkyl-2-haloaniline derivatives are intermediates for the synthesis of compounds useful as pharmaceuticals or agricultural chemicals.
2. Related Art
It is known that a Friedel-Crafts alkylation reaction of an aniline derivative does not proceed without difficulty. The reason for this difficulty is as follows. In general, in the Friedel-Crafts alkylation reaction of an aniline derivative, a protonic acid or a Lewis acid is used as a catalyst. This catalyst, together with an amino group in the aniline derivative, forms a salt or coordinate bond to lower electron density on the aromatic ring, resulting in lowered reaction rate. In particular, it is known that, in the alkylation of a 2-haloaniline derivative, an electron withdrawing substituent effect of a halogen atom in an ortho position on the aromatic ring relative to the amino group makes it very difficult for the alkylation reaction to proceed.
In order to solve the above problem, two methods have been proposed.
In one of the two methods, the amino group in the 2-haloaniline derivative is first protected with a protective group, such as acetyl, to lower the capability of the amino group that the amino group combines with the protonic acid or the Lewis acid to form a salt or complex bond. Thereafter, the Friedel-Crafts alkylation of the protected 2-haloaniline derivative is carried out. So far as the present inventors know, however, there is no report about successful preparation of a product in which the regioselectivity has been significantly enhanced by this method.
The other method is disclosed in Japanese Patent Laid-Open Publication No. 944/1983. In this method, a 2-haloaniline derivative is alkylated in a closed vessel at a high temperature of 175 to 250° C. under a pressure of 5 to 50 atm to selectively prepare a derivative in which an alkyl group has been introduced into the para or ortho position of the 2-haloaniline derivative.
In this method, however, the alkylation should be carried out under acidic conditions and, at the same time, under high temperature and high pressure conditions. For this reason, in carrying out the reaction, a pressure-resistant and acid-resistant closed vessel should be used. This is disadvantageous from the viewpoint of handleability on a commercial scale. Due to the above reaction conditions, substrates usable in this reaction are disadvantageously limited to highly thermally stable compounds. Further, in aromatic ring coupling reactions such as Still coupling and Suzuki coupling, which have recently drawn attractive attention, aromatic iodine compounds having low thermal stability are generally used. Therefore, the method described in Japanese Patent Laid-Open Publication No. 944/1983, which requires high temperature conditions, cannot be applied to such iodine compounds without difficulties.
Accordingly, a method for synthesizing an alkylation product under mild reaction conditions without the necessity of adopting severe reaction conditions has been desired.
On the other hand, for example, WO 01/92231 discloses 6-t-butyl-8-fluoroquinoline derivatives as a group of compounds having excellent control activity against rice blast. Thus, 4-alkyl-2-haloaniline derivatives can be used as intermediates for the synthesis of pharmaceuticals or agricultural chemicals. When a 4-alkyl-2-haloaniline derivative is synthesized for use in the above applications, the 4-alkyl-2-haloaniline derivative is preferably prepared by an alkylation reaction with high regioselectivity from the viewpoints of the quality and productivity of the final product.